Method of and material for purification of physiological liquids of organism, and method of producing the material

ABSTRACT

A method of purification of physiological liquids of organism has the step of passing a physiological liquid through a material which has a size, a shape, and a structure selected so as to remove toxic compounds from the physiological liquid and is composed of a partially chloromethylated porous highly crosslinked styrene or divinylbenzene copolymerwhich initially have surface exposed chloromethyl groups in which thereafter chlorine is replaced with an element which forms different surface exposed functional groups with a greater hydrophilicity and greater biocompatibility than that of the chloromethyl group.

BACKGROUND OF THE INVENTION

The present invention relates to a method of and material forpurification of physiological liquids of organism, and method ofproducing the material.

It is well known that physiological liquids of organisms such as blood,plasma, peritoneal liquid etc., accumulate and transport varioustoxicants in the case of poisoning the organism as well as in the caseof diseases, in particular diseases of liver and kidneys. It istherefore advisable to remove the toxicants from the physiologicalliquids to significantly improve the situation of the patient. Aplurality of methods have been invented and have been utilized forremoving toxicants from blood, plasma and other physiological liquids.One of the most efficient methods is hemodialysis. This method, however,is generally restricted to removing small toxic molecules, whereastoxins belonging to the so-called middle-size molecules (between 500 and30000 Dalton molecular weight) are eliminated too slowly, even withmodern "high flux" dialyser membranes. It is believed to be advisable tofurther improve the existing methods so as to provide an efficientpurification of the physiological liquid of organism, especially withrespect to above toxicants having larger molecular sizes, for thepurpose of preventing propagation of diseases or curing the disease.Some solutions were disclosed in our earlier patent application Ser. No.08/756,445.

SUMMARY OF THE INVENTION

Accordingly, it is an object of present invention to provide a method ofand a material for purification of physiological liquids of organism,and method of producing the material, which are further improvements inthe above specified field.

In accordance with the present invention, the method of purification ofphysiological liquids of organism comprises removing a physiologicalliquid containing toxicants from a patient, passing the physiologicalliquid through a material which has a size, a shape, and a structureselected so as to remove toxic compounds from the physiological liquidand is composed of a partially chloromethylated porous highlycrosslinked styrene or divinylbenzene copolymer which initially havesurface exposed chloromethyl groups in which thereafter chlorine isreplaced with an element which forms different surface exposedfunctional groups with a greater hydrophilicity and greaterbiocompatibility than that of the chloromethyl group.

In accordance with a further feature of present invention, the materialfor purification of physiological liquids of organism is proposed, whichmaterial has a size, a shape, and a structure selected so as to removetoxic compounds from the physiological liquid and is composed of apartially chloromethylated porous highly crosslinked styrene ordivinylbenzene copolymer which initially have surface exposedchloromethyl groups in which thereafter chlorine is replaced with anelement which forms different surface exposed functional groups with agreater hydrophilicity and greater biocompatibility than that of thechloromethyl group.

Finally, a method for producing the material for purification ofphysiological liquids of organism is proposed, in accordance with whichthere is proposed a material which has a size, a shape, and a structureselected so as to remove toxic compounds from the physiological liquidand is composed of a partially chloromethylated porous highlycrosslinked styrene or divinylbenzene copolymer which initially havesurface exposed chloromethyl groups in which thereafter chlorine isreplaced with an element which forms different surface exposedfunctional groups with a greater hydrophilicity and greaterbiocompatibility than that of the chloromethyl group.

In accordance with a preferable embodiment of the present invention, thepore size of the material is selected as being in the range between 1and 15 nm and the structure of the material is selected such thathydrophobic surface in the above pores should be exposed to middle-sizemolecules. Thus, hydrophobic microporous and mesoporous polymericmaterials are best suited for removing toxicants such as for examplebeta-2 microglobulin and others. These materials may also containtransport-enhancing macropores which surface, however, must be madebiocompatible, just like the other surface of the polymer material. Whenthe method is performed in accordance with present invention, itprovides for an efficient removal of broad range of toxicants fromblood, plasma and other physiological liquids of organism.

The novel features which are considered as characteristic for thepresent invention are setforth in particular in the appended claims. Theinvention itself, however, both as to its construction and its method ofoperation, together with additional objects and advantages thereof, willbe best understood from the following description of specificembodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with present invention, a purification of physiologicalliquids of organism by removing toxicants, and other physiologicalliquids of organism from blood is proposed. A patient's blood iswithdrawn from an arterial blood circulatory access point, past througha polymer which removes toxicants, and re-enters the patient through avenous access point. The polymer has such a pore size and a structurewhich provides the removal of beta-2 microglobulin. More particularly,the pore size of the polymer is within the range 1-15 nm.

The polymers impression can be styrenic, acrylic, or any other polymerssatisfying the above mentioned conditions.

One example of the material through which the blood can be passed forpurification of physiological liquids of organism is a sorbent forremoving toxicants from blood or plasma, which has a plurality of beadsof hypercrosslinked polystyrene resin, which beads have a surfacemodified so as to prevent adsorption of large proteins and platelet andto minimize activation of blood complement system, without affectionnoticeably the accessability of the inner adsorption space of the beadsfor small and middle-size toxicant molecules.

To achieve the desired chemical modification of the bead surface, whichare intended to enhance the hemocompatibility of the material, onepossible approach is the formation of lipid-like layers on the surfaceof polystyrene beads, which should simulate the structure ofbiomembranes. Copolymers of 2-methacryloyloxyethyle-phosphorylcholinewith n-butyl-methacrylate can be grafted on the surface of materials.The copolymer was shown to adsorb free phospholipids from blood to forman organized structure similar to that of a bilayer membrane. It isbelieved that membrane-like surfaces are thus formed which reduceadsorption of proteins and platelet from blood and make the materialmore biocompatible. In our approach, groups of phosphatidylcholine areformed on the surface of polystyrene beads, without a preliminarygrafting of the hydrophilic copolymer suggested by Ishihara, et al.

Second approach consists of depositing heparin on the surface of thepolystyrene beads. This can be done in several ways, including (I)chemical covalent binding of heparin to the polystyrene chains on thesurface of beads, or (ii) electrostatic adsorption of heparin molecules,which are negatively charged, to positively charged ionogenic groupsintroduced into the surface layer of the beads. Heparin inhibitsactivation of the blood complement system and prevents formation ofclots.

Still another approach consists of binding long hydrophilic polymerchains on the beads surface, which should prevent contacts between bloodproteins and cells with the hydrophobic polystyrene surface.

Finally, the fourth approach is depositing high molecularweightfluorinated polyalkoxyphosphazene on the outer surface of the beads.Phosphazene represents the best biocompatible polymeric material.Modification of the sorbent surface consists in contacting thepolystyrene beads with an appropriate amount of a solution of thepolyphosphazene in an organic solvent. Due to the ability of thehypercrosslinked polystyrene to strongly swell with the solvent, thelatter appears completely incorporated into the beads after a shortperiod of time, whereas the dissolved polyphosphazene remains depositedon the surface of beads. The solvent incorporated into the beads is thenremoved by heating the beads under reduced pressure. The large size ofpolyphosphazene molecules used in this procedure prevents theirpenetration into the pores of the beads. Therefore, the whole of theinternal surface of the material remains active and accessible to bloodtoxicants, whereas the outer surface exposes to blood proteins and cellsthe insoluble in water and biocompatible polyphosphazene.

The chemical modification of the surface of sorbent beads, which is thecase in the first three of the above modification approaches, isfacilitated by the remarkable peculiarity of the hypercrosslinkedpolystyrene, namely, that the reactive functional groups of the polymerare predominantly located on its surface. The hypercrosslinkedpolystyrene is generally prepared by crosslinking polystyrene chainswith large amounts of bifunctional compounds, in particular, thosebearing two reactive chloromethyl groups. The latter alkylate, in a twostep reaction, two phenyl groups of neighboring polystyrene chainsaccording to Friedel-Crafts reaction with evolution of two molecules ofHCl and formation of a cross bridge. During the crosslinking reaction,the three-dimensional network formed acquires rigidity. This propertygradually reduces the rate of the second step of the crosslinkingreaction, since the reduced mobility of the pending second functionalgroup of the initial crosslinking reagent makes it more and moredifficult to find an appropriate second partner for the alkylationreaction. This is especially characteristic of the second functionalgroups which happen to be exposed to the surface of the bead. Therefore,of the pending unreacted chloromethyl groups in the finalhypercrosslinked polymer, the largest portion, if not the majority ofthe groups, are located on the surface of the bead (or on the surface oflarge pores). This circumstance makes it possible to predominantlymodify the surface of the polymer beads by involving the abovechloromethyl groups into various chemical reactions which are subject ofthe present invention.

The following examples are intended to illustrate, but not to limit, theinvention. In general, the examples and associated preparation protocolsillustrate the modification of the surface of microporous and biporoushypercrosslinked polystyrene beads prepared by an extensive crosslinkingof corresponding styrene-divinylbenzene coppolymers usingmonochlorodimethyl ether as the bifunctional reagent or using otherconventional chloromethylation and post-crosslinking protocols. Thecontent of residual pending chloromethyl groups in the polystyrene beadsamounts to 0.5-1.0% CL for the microporous and up to 7% for biporousmaterials. The beads of the initial material should preferably bespherical and smooth to minimize possible damages to hematocytes.

The sorbents prepared in accordance with this invention are charged to acolumn or cartridge for service. The column should preferably beprovided with an inlet and an outlet designed to allow easy connectionwith the blood circuit, and with two porous filters set between theinlet and the sorbent layer, and between the sorbent layer and theoutlet. The column may be made of a biocompatible material, glass,polyethylene, polypropylene, polycarbonate, polystyrene. Of these,polypropylene and polycarbonate are preferred materials, because thecolumn packed with the sorbent can be sterilized (e.g., autoclave andgamma-ray sterilization) before use.

The column or cartridge is then filled with a 1% solution of human serumalbumin in normal saline and stored at 4° C. When ready for use, thecolumn is washed with 0.9% NaCl solution to which has been added asuitable anticoagulant such as ACD-A containing heparin in an effectiveamount. For a 250 ml cartridge, this is approximately 11 of the sodiumchloride solution to which 150 ml of ACD-A containing 6,000 units ofheparin has been added.

As usual the following two typical extracorporeal blood circulationsystems can be employed:

(I) Blood taken from a blood vessel of a patient is forced to passthrough a column packed with the sorbent of this invention, and theclarified blood is returned to the blood vessel of the patient.

(ii) Blood taken from a patient is first separated through a separationmembrane, by centrifugation or the like into hemocytes and plasma, theplasma thus separated is then forced to pass through the column packedwith the sorbent of this invention to remove toxicants from the plasma;then, the clarified plasma from the column is mixed with the hemocytesseparated above, and the mixture is returned to the blood vessels of thepatient.

Of these two methods, the latter is more practical because of thesmaller loss of hemocytes, for example, by adhesion of platelets anderythrocytes.

Any other ways of performing hemoperfusion or plasma perfusion areappropriate with the modified sorbents of this invention. Especiallypromising seems to be the above mentioned suggestion of Bodden (U.S.Pat. No. 5,069,662, December 1991), by which high concentrations ofanti-cancer agents are perfused through the liver or other body organcontaining a tumor and then the effluent blood is subjected to theextracorporeal hemoperfusion to remove the excess of the drug before theblood is returned to the blood circulation system of the patient.Another perspective system is that by Shettigar, et al. (U.S. Pat. No.5,211,850, 1993), where achieving both convective and diffusivetransport of plasma across a hollow fiber membrane towards a closedchamber with a sorbent and back into the fiber channel was suggested 2E.The chamber could be packed with the sorbent of this invention.

In general, the modified hypercrosslinked polystyrene sorbents of thepresent invention are intended to replace in hemoperfusion and plasmaperfusion procedures all kinds of activated carbons. The new material ismechanically stable and does not release fines causing embolia; it ismuch more hemocompatible, exhibits higher sorption capacities toward abroad range of blood toxicants, and can, in principle, be regeneratedand reused.

The adsorption spectrum of modified hypercrosslinked polystyrenesorbents of this invention extends to substances with molecular weightsof between 100 and 20,000 daltons. The maximum adsorption is ofmolecules with weight of between 300 and 5,000 daltons, identifiedclinically as "medium molecules", which are present in abnormalquantities in ureamic and many others patients and are incompletelyremoved by conventional hemodialysis procedures. Such compounds ascreatinine, barbiturate, phenobarbital, sodium salicylate, amphetamines,morphine sulfate, meprobamate, glutethimide, etc. can be effectively andrapidly removed from the blood using both microporous and biporoussorbents. (To avoid removal of useful drugs from blood duringhemoperfusion on the new sorbents, the latter can be previouslysaturated with the corresponding drug to an appropriate level). Inaddition to removal of small and medium molecules, the biporous sorbentsalso shows an excellent ability to absorb cytochrom C andbeta-2-microglobulin(molecular weight of about 20,000 daltons) as wellas vitamin B12.

Preparation of initial hypercrosslinked polystyrene to a solution of87.6 g xylylene dichloride (0.5 mol) in 600 ml dry ethylene dichloride104 g (l mol) of styrene copolymer with 0.5% divinylbenzene were added,the suspension was agitated for 1 hr and supplied with a solution of116.8 ml tinn tetrachloride (l mol) in 100 ml ethylene dichloride. Thereaction mixture was then heated for 10 hrs at 80° C., the polymer wasfiltrated and carefully washed with aceton, a mixture of aceton with 0.5N HCl, 0.5 N HCl and water until no chlorine ions were detected in thefiltrate. The product dried in vacuum represented microporoushypercrosslinked polystyrene. It contained 0.65% pendant unreactedchlorine and displayed an inner surface area as high as 980 m2/g.

To a suspension of 104 g (l mol) of a macroporous styrene copolymer with4% divinylbenzene in 500 ml dry ethylene dichloride a solution of 76 ml(l mol) monochlorodimethyl ether and 116.8 ml (l mol) tinn tetrachloride(l mol) in 100 ml ethylene dichloride was added. The mixture was thenheated at 80° for 10 hrs, the polymer was filtrated and carefully washedwith aceton, a mixture of aceton with 0.5 N HCl, 0.5 N HCl and wateruntil no chlorine ions were detected in the filtrate. The product driedin vacuum represented biporous hypercrosslinked polystyrene andcontained 3.88% pendent unreacted chlorine. The above extensivecrosslinking resulted in the increase of its inner surface area from 120to 1,265 m2/g.

Formation of Lipid-like Surface Structures

EXAMPLE 1

To a dispersion of 10 g biporous polymer in 30 ml of a dioxanemethanolmixture (5:1, vol/vol) a solution of 1 g Nal and 6 ml of 2-ethanol aminein 1 ml of the same mixed solvent was added, and heated at 80° C. for 9hrs. The polymer was filtered, washed with the dioxane-methanol mixture,methanol 0.1 N HCl (in order to protonate the secondary amino groups)and finally rinsed with water and 50 ml methanol. To the polymer, driedin vacuum, 25 ml of dry pyridine were added and then 1 ml POCl3 in 5 mldry pyridine. The reaction mixture was kept for 15 hrs at ambienttemperature, filtered, the polymer was rinsed with dry pyridine and witha solution of 1.4 g choline chloride in 25 ml dry dimethyl sulfoxide at40° C. The mixture was heated to 60° C. for 4 hrs, kept at ambienttemperature for 15 hrs, provided with 5 ml dry pyridine and, afteradditional 5 hrs, washed carefully with distilled water and rinsed withethanol. The resin was kept in ethanol at 5° C. before use.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 2

3 g of the biporous polymer treated with 2-ethanol amine and activatedwith POCl3 as described in Example 1 were treated with a solution of 0.3g tert.-butyl-oxycarbonyl-L-serine in 2 ml dry pyridine at ambienttemperature for 15 hrs, washed with ethyl acetate, dioxane, water andmethanol and then dried. The protection BOC-groups were removed with 5ml trifluoroacetic acid in 1 hr at ambient temperature. The finalproduct was washed with ether, ethanol and water.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 3

4 g of the biporous hypercrosslinked polymer were allowed to swell with16 ml of an 8% solution of NaOH in ethylene glycol and then heated to180° C. for 5 hrs, in order to substitute the residual chloromethylgroups with ethylene glycol groups. The polymer was washed with ethanol,water, aceton and dried under vacuum. The dry polymer was then activatedwith POCl3 and reacted with choline chloride as described in Example 1.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 4

4 g of the biporous hypercrosslinked polymer were modified with ethyleneglycol as described in Example 13, activated, with POCl3 as described inExample 1 and reacted with a mixture of 3 ml glacial acetic acid and 3ml 2-ethanol amine at ambient temperature for 3 days. The product waswashed with pyridine, water and ethanol.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

Depositing Heparin on the Surface

EXAMPLE 5

The product of reacting the initial biporous polymer with 2-ethanolamine according to Example 1 was washed with 0.5 1 0.1 N HCl and water,provided with 5 ml of aqueous heparin solution (5,000 U/ml) and kept for15 hrs at ambient temperature and for 4 hrs at 5° C. The polymer withthe ionically absorbed heparin was filtered from the excess solution andkept in ethanol at 5° C. before use.

Microporous Hypercrosslinked Polymer was Modified by Exactly the sameProcedure.

EXAMPLE 6

The heparin absorbed on the polymer according to Example 5 was bondedcovalently by treating the polymer for 4 hrs with an aqueous solution ofglutare dialdehyde (2.0 ml of a 25% solution for 1 g of the wetpolymer). The pendant aldehyde groups were coupled then with L-asparticacid (0.2 g L-Asp in 3 ml 1 N NaOH for 1 g polymer) for 14 hrs. Thepolymer washed with 0.1 N NaOH and water was kept in ethanol at 5° C.before use.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 7

The heparin absorbed on the polymer according to Example 5 was bondedcovalently by washing the polymer with 500 ml dry methanol, 200 ml drydioxane and treating it for 5 hrs with a solution of 0.1 g hexamethylenediisocyanate in 3 ml dioxane (for 1 g polymer). The polymer wasfiltered, washed with dioxane and the pendant isocyanate groups coupledwith L-aspartic acid by treating the polymer with 1 gtris-trimethylsilyl derivative of L-Asp in 3 ml heptane for 15 hrs atambient temperature. The polymer was washed with heptane, methanol, 0.1N NaOH and water and kept in ethanol at 5° C. before use.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 8

1 g of the product of reacting the initial biporous polymer with2-ethanol amine according to Example 1 was washed with water and treatedwith 4 ml 25% aqueous solution of glutare dialdehyde for 5 hrs atambient temperature. Excess of the reagent was then removed with waterand the polymer was supplied with 2.5 ml of heparin solution (5,000U/ml) for 15 hrs at ambient temperature and finally rinsed with water.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 9

1 g of the product of reacting the initial biporous polymer with2-ethanol amine according to Example 1 was washed with methanol, driedin vacuum, swelled with dioxane and supplied with a solution of 0.1 ghexamethylene diisocyanate in 3 ml dioxane. After 10 hrs. the productwas washed with dry dioxane and dimethyl sulfoxide and treated with 2.5ml of an aqueous solution of heparin (5,000 U/ml) for 3 days. The excessheparin was removed with water and the polymer was kept in ethanol at50° C. before use.

Microporous Hypercrosslinked Polymer was Modified by Exactly the sameProcedure.

Modification with Hydrophilic Polymers

EXAMPLE 10

1 g of the product of reacting the initial biporous polymer with2-ethanol amine and activating it with glutare dialdehyde according toExample 8 was treated with 2 ml aqueous solution of 0.16 g polyethyleneglycol (molecular weight 20,000) for 3 days at ambient temperature andthen carefully washed with water.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 11

1 g of the product of reacting the initial biporous polymer with2-ethanol amine and activating it with hexamethylene diisocyanateaccording to example 9 was treated with 2 ml aqueous solution of 0.16 gpolyethylene glycol (molecular weight 20,000) for 3 days at ambienttemperature and then carefully washed with water.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 12

4 g of biporous hypercrosslinked polymer was allowed to swell with 16 mlof an 8% solution of NaOH in ethylene glycol and then heated to 180° C.for 5 hrs, in order to substitute the residual chloromethyl groups withethylene glycol groups. The polymer was washed with ethanol, water,aceton and dried under vacuum. 2 g of dry polymer, swollen with drydioxane, were activated with hexamethylene diisocyanate as described inExample 9, washed with dry dioxane and supplied with a solution of 1.2 gpolyethylene glycol (molecular weight 40,000) in 10 ml dry dimethylsulfoxide, heated at 80° C. for 6 hrs and washed with ethanol and water.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 13

2 g of the ethylene glycol-modified polymer prepared according toExample 12 were activated with glutare dialdehyde according to theprocedure described in Example 8 and treated with a solution of 1.2 gpolyethylene glycol (molecular weight 40,000) in 10 ml water for 1 dayat ambient temperature. The polymer was washed then with ethanol andwater.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 14

To 3 g of dry biporous polymer, swollen with dry benzene, were added 15ml of a solution containing 8 g alcoholate of polyethylene glycol(molecular weight 12,000) in dry benzene and the mixture was boiledunder an argon atmosphere and adding small pieces of sodium as long asthe latter dissolved in the reaction mixture (about 10 hrs). Afteradditional two days at room temperature, the polymer was carefullywashed with ethanol.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 15

According to the procedure described in Example 14, 1 g of the polymerwere treated with 1 g of the alcoholate of polyethylene glycol of lowermolecular weight (6,000).

EXAMPLE 16

To a solution of 0.2 g polyethylene glycol (molecular weight 12,000) in4 ml dry benzene were added first 0.1 ml of hexamethylene diisocyanateand then, after 2 hrs, 2 g of dry biporous polymer which was previouslymodified with ethylene glycol according to the procedure described inExample 12.

Microporous Hypercrosslinked Polymer was Modified by Exactly the SameProcedure.

EXAMPLE 17

Procedure described in Example 16 was repeated with polyethylene glycolof lower molecular weight (6,000).

EXAMPLE 18

0.2 g chitosan were dissolved in 6 ml concentrated acetic acid and addedto 2 g of dry biporous polymer. After 2 hrs, 10 ml of cold 30% NaOHsolution were slowly added to the above mixture, the polymer wasseparated from the reaction mixture, rinsed with water, dehydrated withmethanol, dried and heated to 80° C. with 10 ml of a solution of 0.1 gNal in a dioxane-methanol mixture (5:1, vol/vol) for 8 hrs, in order toaccomplish alkylation of the chitosan amino groups by chloromethylgroups of the polymer. The final product was washed with aqueous aceticacid and then ethanol.

Microporous Hypercrosslinked Polymer was Modified Exactly the SameProcedure.

Coating with Phosphazene

EXAMPLE 19

A solution of 0.0009 g poly(trifluoroethoxyy) phosphazene (molecularweight 10⁷) in 8 ml ethyl acetate were added quickly to 3 g of drybiporous polymer and agitated until the whole of the solvent was totallyabsorbed by the polymer beads. The material was then dried under reducedpressure and washed with ethanol.

EXAMPLE 20

A solution of 130 g p-ethylstyrene, 132 g divinylbenzene (a mixture ofpara and metha-isomers of about 1:1) and 2.62 g benzoyl peroxide in amixture of 600 ml toluene and 100 ml iso-amyl alcohol was suspended in 4liters of pure water containing 1% cellulose stabilizer. After 39 minstirring at room temperature, the mixture was heated at 40° C. for 1hours, 60° C. for 2 hours, 80° C. for 5 hours and 96° C. for 2 hours.After cooling the mixture to room temperature, the beads obtained werefiltered and washed with hot water, methanol and water. The polymer wasdried in oven at 80° C. within one day. 10 g of the polymer obtainedwere treated with a solution of 10 ml monochloridmethyl ether and 2 gZnCl2 of 30 ml ethylene dichloride for 5 h at ambient temperature toincorporate 5.2% chlorine due to a partial chloromethylation. Thusschlormethylated producted was in Example 1 and, finally, coated withpoly(trifluorethoxy) phosphazene as described in Example 19.

The above presented description disclosed the use for purification ofphysiological liquids of a material which has a plurality of beads.However, other materials also can be used for this purpose, such as forexample fiber materials. The fiber materials are composed of a pluralityof polymer fibers with a surface modified so as to prevent adsorption ofmuch proteins and platelet and to minimize activation of bloodcomplement system without affection noticeably the accessibility of theinner adsorption space of the fibers for small and middle-size toxicantmolecules.

It will be understood that each of the elements described above, or twoor more together, may also find a useful application in other types ofproducts and methods differing from the types described above.

While the invention has been illustrated and described as embodied in amethod of and material for purification of physiological liquids oforganism, and method of producing the material it is not intended to belimited to the details shown, since various modifications and structuralchanges may e made without departing in any way from the spirit of thepresent invention.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed as new and desired to be protected by letters patent isset forth in the appended claims.

What is claimed is:
 1. A material for purification of physiologicalliquids of organism, comprising a polymeric material which has a size, ashape, and a structure selected so as to remove toxic compounds from thephysiological liquid and is composed of a partially chloromethylatedporous highly crosslinked styrene or divinylbenzene copolymer whichinitially have surface exposed chloromethyl groups in which thereafterchlorine is replaced with an element which forms different surfaceexposed functional groups with a greater hydrophilicity and greaterbiocompatibility than that of chloromethyl groups, said surface exposedfunctional groups of greater hydrophilicity and enhancedbiocompatibility being covalently bonded lipid-like structures selectedfrom a group consisting of phosphatidyl choline, phosphatidyl serine,and phosphatidyl 2-ethanol amine.
 2. A material as defined in claim 1,wherein said polymeric material has polymer beads with mainlyunsubstituted hydrophobic interior which is responsible for removing oftoxic compounds in a molecular range of 300 to 2000 Dalton.
 3. Amaterial as defined in claim 1, wherein said porous highly crosslinkedstyrene or divinylbenzene copolymer is a macroporous or mesoporousstyrene-divinylbenzene-ethylstyrene copolymer subjected to a partialchloromethylation to a chlorine content of up to 7%.
 4. A material asdefined in claim 1, wherein said porous highly crosslinked styrene ordivinylbenzene copolymer is a hypercrosslinked polystyrene produced fromcrosslinked styrene copolymers by an extensive chloromethylation and asubsequent post-crosslinking by treating with a Friedel-Crafts catalystin a swollen state.
 5. A material as defined in claim 1, wherein saidporous highly crosslinked styrene or divinylbenzene copolymer is ahypercrosslinked polystyrene produced from crosslinked styrenecopolymers by an extensive additional post-crosslinking in a swollenstate with bifunctional crosslinking agents selected from the groupconsisting of monochlorodimethyl ether and p-xylilene dichoride.
 6. Amethod of producing a material for purification of physiological liquidsof organism, comprising the steps of providing a polymeric materialwhich has a size, a shape, and a structure selected so as to removetoxic compounds from the physiological liquid and is composed of apartially chloromethylated porous highly crosslinked styrene ordivinylbenzene copolymer which initially have surface exposedchloromethyl groups; and replacing chlorine in the chloromethyl groupswith an element which forms different surface exposed functional groupswith a greater hydrophilicity and greater biocompatibility than that ofthe chloromethyl group, said replacing including reacting the surfaceexposed to chloromethyl groups of said porous highly crosslinked styreneor divinylbenzene copolymer with amines selected from a group consistingof 2-ethanol amine, ethylamine and dimethylamine, followed byelectrostatically binding heparin from its aqueous solution onto thesurface of the beads or by depositing high molecular weight polybis(trifluoroethoxy) phosphazene, by treating the beads with a solution ofphosphazene in an organic solvent and evaporating the solvent.
 7. Amethod of producing a material for purification of physiological liquidsof organism, comprising the steps of providing a polymeric materialwhich has a size, a shape, and a structure selected so as to removetoxic compounds from the physiological liquid and is composed of apartially chloromethylated porous highly crosslinked styrene ordivinylbenzene copolymer which initially have surface exposedchloromethyl groups; and replacing chlorine in the chloromethyl groupswith an element which forms different surface exposed functional groupswith a greater hydrophilicity and greater biocompatibility than that ofthe chloromethyl group, said replacing including substituting thesurface exposed chloromethyl groups of said porous highly crosslinkedstyrene or divinylbenzene copolymer with ligands selected from the groupconsisting of 2-ethanol amine ligands orethylene glycol ligands,activating the ligands with phosorus oxychloride, and covalently bindinghydrophilic moieties selected from the group consisting of choline,serine and 2-ethanol amine.